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Published on: May 11, 2018
Response of plasma microRNAs to nusinersen treatment in patients with SMA
Irina T Zaharieva1, Mariacristina Scoto1,2, Karolina Aragon-Gawinska3,4
1Developmental Neurosciences Research and Teaching Department, Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK.
Objective:
Spinal muscular atrophy (SMA) is a common genetic cause of infant mortality. Nusinersen treatment ameliorates the clinical outcome of SMA, however, some patients respond well, while others have limited response. We investigated microRNAs in blood samples from SMA patients and their response to nusinersen treatment evaluating the potential of circulating microRNAs as biomarkers for SMA.
Methods:
In a discovery cohort study, microRNA next-generation sequencing was performed in blood samples from SMA patients (SMA type 2, n = 10; SMA type 3, n = 10) and controls (n = 7). The dysregulated microRNAs were further analysed in the therapeutic response cohort comprised of SMA type 1 patients (n = 22) who had received nusinersen treatment, at three time points along the treatment course (baseline, 2 and 6 months of treatment). The levels of the studied microRNAs were correlated to the SMA clinical outcome measures.
Results:
In the discovery cohort, 69 microRNAs were dysregulated between SMA patients and controls. In the therapeutic response cohort, the baseline plasma levels of miR-107, miR-142-5p, miR-335-5p, miR-423-3p, miR-660-5p, miR-378a-3p and miR-23a-3p were associated with the 2 and 6 months response to nusinersen treatment. Furthermore, the levels of miR-107, miR-142-5p, miR-335-5p, miR-423-3p, miR-660-5p and miR-378-3p at 2 months of treatment were associated with the response after 6 months of nusinersen treatment.
Interpretation:
Blood microRNAs could be used as biomarkers to indicate SMA patients' response to nusinersen and to monitor the efficacy of the therapeutic intervention. In addition, some of these microRNAs provide insight into processes involved in SMA that could be exploited as novel therapeutic targets.
Insights
Circulating microRNAs in blood show potential as biomarkers for spinal muscular atrophy (SMA) patients, predicting response to nusinersen treatment. These microRNAs can monitor treatment efficacy and may offer new therapeutic targets for SMA.
Area of Science:
- Genetics and Molecular Biology
- Neurology
- Biomarker Discovery
Background:
- Spinal muscular atrophy (SMA) is a significant genetic cause of infant mortality.
- Nusinersen treatment improves SMA outcomes, but patient responses vary.
- Identifying reliable biomarkers is crucial for personalized SMA treatment.
Purpose of the Study:
- To investigate circulating microRNAs (miRNAs) in SMA patients.
- To evaluate the potential of these miRNAs as biomarkers for nusinersen treatment response.
- To correlate miRNA levels with clinical outcomes in SMA.
Main Methods:
- MicroRNA next-generation sequencing in blood samples from SMA patients and controls.
- Analysis of dysregulated miRNAs in a cohort of SMA type 1 patients undergoing nusinersen treatment.
- Correlation of miRNA levels with clinical outcome measures at multiple time points.
Main Results:
- 69 miRNAs were found to be dysregulated between SMA patients and controls.
- Specific baseline plasma miRNAs (e.g., miR-107, miR-142-5p) correlated with nusinersen treatment response at 2 and 6 months.
- Early miRNA levels (2 months) predicted later treatment response (6 months).
Conclusions:
- Blood-based microRNAs can serve as biomarkers for predicting and monitoring SMA patient response to nusinersen.
- These miRNAs offer insights into SMA pathogenesis.
- Potential for novel therapeutic targets based on identified miRNAs.
